title: A small volatile bacterial molecule triggers mitochondrial dysfunction in murine skeletal muscle.
abstract: Mitochondria integrate distinct signals that reflect specific threats to the host, including infection, tissue damage, and metabolic dysfunction; and play a key role in insulin resistance. We have found that the Pseudomonas aeruginosa quorum sensing infochemical, 2-amino acetophenone (2-AA), produced during acute and chronic infection in human tissues, including in the lungs of cystic fibrosis (CF) patients, acts as an interkingdom immunomodulatory signal that facilitates pathogen persistence, and host tolerance to infection. Transcriptome results have led to the hypothesis that 2-AA causes further harm to the host by triggering mitochondrial dysfunction in skeletal muscle. As normal skeletal muscle function is essential to survival, and is compromised in many chronic illnesses, including infections and CF-associated muscle wasting, we here determine the global effects of 2-AA on skeletal muscle using high-resolution magic-angle-spinning (HRMAS), proton ((1)H) nuclear magnetic resonance (NMR) metabolomics, in vivo (31)P NMR, whole-genome expression analysis and functional studies. Our results show that 2-AA when injected into mice, induced a biological signature of insulin resistance as determined by (1)H NMR analysis-, and dramatically altered insulin signaling, glucose transport, and mitochondrial function. Genes including Glut4, IRS1, PPAR-γ, PGC1 and Sirt1 were downregulated, whereas uncoupling protein UCP3 was up-regulated, in accordance with mitochondrial dysfunction. Although 2-AA did not alter high-energy phosphates or pH by in vivo (31)P NMR analysis, it significantly reduced the rate of ATP synthesis. This affect was corroborated by results demonstrating down-regulation of the expression of genes involved in energy production and muscle function, and was further validated by muscle function studies. Together, these results further demonstrate that 2-AA, acts as a mediator of interkingdom modulation, and likely effects insulin resistance associated with a molecular signature of mitochondrial dysfunction in skeletal muscle. Reduced energy production and mitochondrial dysfunctional may further favor infection, and be an important step in the establishment of chronic and persistent infections.
authors.affiliation: Department of Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts, United States of America ; Athinoula A. Martinos Center of Biomedical Imaging, Massachusetts General Hospital, Boston, Massachusetts, United States of America ; Shriners Hospitals for Children Boston, Boston, Massachusetts, United States of America.
authors.forename: A Aria
authors.initials: AA
authors.lastname: Tzika
authors.forename: Caterina
authors.initials: C
authors.lastname: Constantinou
authors.forename: Arunava
authors.initials: A
authors.lastname: Bandyopadhaya
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Psychogios
authors.forename: Sangseok
authors.initials: S
authors.lastname: Lee
authors.forename: Michael
authors.initials: M
authors.lastname: Mindrinos
authors.forename: J A Jeevendra
authors.initials: JA
authors.lastname: Martyn
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Tompkins
authors.forename: Laurence G
authors.initials: LG
authors.lastname: Rahme
mesh_terms: D000098:Acetophenones / Q000378:metabolism / Q000633:toxicity*; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D015153:Blotting, Western; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D009682:Magnetic Resonance Spectroscopy; D055432:Metabolomics; D051379:Mice; D046228:Microarray Analysis; D028361:Mitochondrial Diseases / Q000139:chemically induced* / Q000382:microbiology* / Q000503:physiopathology*; D018482:Muscle, Skeletal / Q000503:physiopathology*; D011550:Pseudomonas aeruginosa / Q000502:physiology*; D053038:Quorum Sensing / Q000502:physiology; D013778:Tetrazolium Salts; D013844:Thiazoles
chemical_list: D000098:Acetophenones; D013778:Tetrazolium Salts; D013844:Thiazoles; D000255:Adenosine Triphosphate; C022616:thiazolyl blue; C038699:acetophenone